Clinical Trial Results:
LIBERTY 2: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered with and without Low-Dose Estradiol and Norethindrone Acetate in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids
Summary
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EudraCT number |
2016-005113-50 |
Trial protocol |
HU CZ BE PL |
Global end of trial date |
10 Jul 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jun 2020
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First version publication date |
28 Jun 2020
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MVT-601-3002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03103087 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Myovant Sciences GmbH
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Sponsor organisation address |
Viaduktstrasse 8, Basel, Switzerland, 4051
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Public contact |
Clinical Trials at Myovant, Myovant Sciences GmbH, +1 650 238 0250, clinicaltrials@myovant.com
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Scientific contact |
Senior VP of Clinical Development, Myovant Sciences GmbH, +1 650 238 0250, LIBERTY@myovant.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
31 Jan 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Jul 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Jul 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To determine the benefit of relugolix 40 milligrams (mg) once daily co-administered with estradiol (E2) 1.0 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Jan 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 17
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Country: Number of subjects enrolled |
Belgium: 4
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Country: Number of subjects enrolled |
Czech Republic: 9
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Country: Number of subjects enrolled |
Hungary: 22
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Country: Number of subjects enrolled |
United States: 284
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Country: Number of subjects enrolled |
Brazil: 5
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Country: Number of subjects enrolled |
Chile: 24
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Country: Number of subjects enrolled |
South Africa: 17
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Worldwide total number of subjects |
382
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EEA total number of subjects |
52
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
382
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 99 study centers throughout the world, including centers in the United States, Belgium, Brazil, Chile, Czech Republic, Hungary, Poland, and South Africa. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 382 premenopausal women aged 18 to 50 years old (inclusive) with heavy menstrual bleeding (≥ 160 millilitres [mL] during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the alkaline hematin method) associated with uterine fibroids were randomized. One participant was randomized in error before eligibility confirmed. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Relugolix plus E2/NETA (Group A) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Relugolix co-administered with E2/NETA for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Relugolix
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Investigational medicinal product code |
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Other name |
TAK-385, MVT-601
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Relugolix (40 mg) tablet administered orally for 24 weeks.
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Investigational medicinal product name |
Estradiol/Norethindrone Acetate
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Investigational medicinal product code |
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Other name |
E2/NETA, low-dose hormonal add-back
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily for 24 weeks.
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Arm title
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Relugolix plus Delayed E2/NETA (Group B) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Relugolix
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Investigational medicinal product code |
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Other name |
TAK-385, MVT-601
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Relugolix (40 mg) tablet administered orally for 24 weeks.
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Investigational medicinal product name |
Estradiol/Norethindrone Acetate
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Investigational medicinal product code |
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Other name |
E2/NETA, low-dose hormonal add-back
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
E2 (1.0 mg)/NETA (0.5 mg) a co-formulated capsule administered orally once daily for the last 12 weeks of treatment.
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Investigational medicinal product name |
Estradiol/Norethindrone Acetate Placebo
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Investigational medicinal product code |
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Other name |
E2/NETA, low-dose hormonal add-back placebo
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily for the first 12 weeks of treatment.
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Arm title
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Placebo (Group C) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Relugolix placebo co-administered with E2/NETA placebo for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Relugolix Placebo
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Investigational medicinal product code |
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Other name |
TAK-385 Placebo, MVT-601 Placebo
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Relugolix (0 mg) placebo tablet administered orally once daily for 24 weeks.
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Investigational medicinal product name |
Estradiol/Norethindrone Acetate Placebo
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Investigational medicinal product code |
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Other name |
E2/NETA, low-dose hormonal add-back placebo
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily for 24 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Relugolix plus E2/NETA (Group A)
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Reporting group description |
Relugolix co-administered with E2/NETA for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Relugolix plus Delayed E2/NETA (Group B)
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Reporting group description |
Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (Group C)
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Reporting group description |
Relugolix placebo co-administered with E2/NETA placebo for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Baseline Analysis Population
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Subject analysis set type |
Modified intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All participants who were randomized to treatment and who received at least 1 dose of study drug.
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End points reporting groups
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Reporting group title |
Relugolix plus E2/NETA (Group A)
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Reporting group description |
Relugolix co-administered with E2/NETA for 24 weeks. | ||
Reporting group title |
Relugolix plus Delayed E2/NETA (Group B)
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Reporting group description |
Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks. | ||
Reporting group title |
Placebo (Group C)
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Reporting group description |
Relugolix placebo co-administered with E2/NETA placebo for 24 weeks. | ||
Subject analysis set title |
Baseline Analysis Population
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All participants who were randomized to treatment and who received at least 1 dose of study drug.
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End point title |
Percentage Of Participants Who Achieved A Menstrual Blood Loss (MBL) Volume Of < 80 mL And A ≥ 50% Reduction From Baseline MBL Volume With Relugolix Plus E2/NETA [1] | ||||||||||||
End point description |
A responder was a participant who had MBL volume of < 80 mL and at least a 50% reduction from baseline MBL volume over the last 35 days of treatment (up to Week 24). All returned feminine products collected at each clinical visit were analyzed by the alkaline hematin method to obtain the MBL volume. MBL volume was measured over the Week 24/early termination feminine product collection interval (up to 35 days prior to the last dose of treatment). The percentage of participants who were responders are presented.
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End point type |
Primary
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End point timeframe |
From Baseline up to last 35 days of treatment (up to Week 24)
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified primary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
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Notes [2] - Modified Intention-to-Treat Population [3] - Modified Intention-to-Treat Population |
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Statistical analysis title |
Number of responders at Week 24 | ||||||||||||
Statistical analysis description |
The primary efficacy analysis was the comparison of the Relugolix plus E2/NETA group with the Placebo group with respect to responder rate.
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Comparison groups |
Relugolix plus E2/NETA (Group A) v Placebo (Group C)
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
< 0.0001 [5] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
56.47
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
46.45 | ||||||||||||
upper limit |
66.49 | ||||||||||||
Notes [4] - Treatment difference is Relugolix plus E2/NETA minus Placebo and unadjusted 95% confidence interval (CI). [5] - P-value was based on Cochran-Mantel-Haenszel test stratified by baseline MBL volume (< 225 mL or ≥ 225 mL) and geographic region (North America or Rest of World). Assessed at a two-sided α = 0.05 significance level. |
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End point title |
Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment [6] | ||||||||||||
End point description |
Amenorrhea was defined as meeting one of the following criteria for 2 consecutive visits:
1. No feminine product returned due to reported amenorrhea;
2. No feminine product returned due to reports of spotting/negligible bleeding coupled with eDiary data indicating infrequent non-cyclic bleeding/spotting;
3. Feminine product collection with a negligible observed MBL volume coupled with eDiary data indicating infrequent non-cyclic bleeding/spotting.
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End point type |
Secondary
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End point timeframe |
From Baseline up to last 35 days of treatment (up to Week 24)
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
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Notes [7] - Modified Intention-to-Treat Population [8] - Modified Intention-to-Treat Population |
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Statistical analysis title |
Achieved Amenorrhea with Relugolix plus E2/NETA | ||||||||||||
Comparison groups |
Relugolix plus E2/NETA (Group A) v Placebo (Group C)
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Number of subjects included in analysis |
254
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Analysis specification |
Pre-specified
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Analysis type |
superiority [9] | ||||||||||||
P-value |
< 0.0001 [10] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
47.3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
38.04 | ||||||||||||
upper limit |
56.56 | ||||||||||||
Notes [9] - Treatment difference is Relugolix plus E2/NETA minus Placebo. 95% CI for difference based on the normal approximation. [10] - P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America or Rest of World). Assessed at a two-sided α = 0.05 significance level. |
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End point title |
Percent Change From Baseline At Week 24 In MBL Volume [11] | ||||||||||||
End point description |
MBL volume was measured using the alkaline hematin method. Least square (LS) means for test of difference is Relugolix plus E2/NETA minus Placebo based on mixed-effect model with treatment, visit, region, Baseline MBL, and treatment by visit interaction included as fixed effects.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Notes [12] - Modified Intention-to-Treat Population [13] - Modified Intention-to-Treat Population |
|||||||||||||
Statistical analysis title |
MBL Volume Percent Change with Relugolix + E2/NETA | ||||||||||||
Comparison groups |
Placebo (Group C) v Relugolix plus E2/NETA (Group A)
|
||||||||||||
Number of subjects included in analysis |
254
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [14] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
-69.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-84.1 | ||||||||||||
upper limit |
-54.3 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
7.58
|
||||||||||||
Notes [14] - P-value for difference was Relugolix plus E2/NETA minus Placebo based on mixed-effect model with treatment, visit, region, Baseline MBL, and treatment by visit interaction included as fixed effects. Assessed at a two-sided α = 0.05 significance. |
|
|||||||||||||
End point title |
Percentage Of Participants With A Hemoglobin Level ≤ 10.5 g/dL At Baseline Who Achieved An Increase Of > 2 g/dL From Baseline At Week 24 [15] | ||||||||||||
End point description |
Blood samples were collected from participants for hemoglobin measurements. Percentages are based on number of participants with hemoglobin ≤ 10.5 gram (g)/decilitre (dL) at Baseline and reported at Week 24.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 24
|
||||||||||||
Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Change in Hemoglobin with Relugolix plus E2/NETA | ||||||||||||
Comparison groups |
Relugolix plus E2/NETA (Group A) v Placebo (Group C)
|
||||||||||||
Number of subjects included in analysis |
68
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [16] | ||||||||||||
P-value |
< 0.0001 [17] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
55.88
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
37.25 | ||||||||||||
upper limit |
74.52 | ||||||||||||
Notes [16] - Treatment difference is Relugolix plus E2/NETA minus Placebo. 95% CI for difference is based on the normal approximation. [17] - P-value based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL). Assessed at a two-sided α = 0.05 significance level. |
|
|||||||||||||
End point title |
Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment [18] | ||||||||||||
End point description |
Uterine fibroid-associated pain was assessed by a pain numerical rating scale (NRS). The pain NRS is a validated, single-item, self-reported measure, which asks respondents to rank their pain on an 11-point scale as follows: 0 (no pain), 1 to 3 (mild pain), 4 to 6 (moderate pain), and 7 to 10 (severe pain).
Participants were asked to document, in an electronic diary, the worst pain associated with their uterine fibroids that they experienced during the last 24 hours, every day until the end of study drug administration. Pain evaluable participants, defined as those who had maximum NRS score ≥ 4 at baseline and had at least 28 days (80% of the last 35 days of treatment) of pain scores recorded in the e-Diary, were analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
From Baseline up to Week 24
|
||||||||||||
Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Pain Assessment with Relugolix plus E2/NETA | ||||||||||||
Comparison groups |
Relugolix plus E2/NETA (Group A) v Placebo (Group C)
|
||||||||||||
Number of subjects included in analysis |
150
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [19] | ||||||||||||
P-value |
< 0.0001 [20] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
29.99
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
15.6 | ||||||||||||
upper limit |
44.38 | ||||||||||||
Notes [19] - Treatment difference is Relugolix plus E2/NETA minus Placebo. 95% CI for difference is based on the normal approximation. [20] - P-value is based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL). Assessed at a two-sided α = 0.05 significance level. |
|
|||||||||||||
End point title |
Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume [21] | ||||||||||||
End point description |
The volume of the primary uterine fibroid was measured by transvaginal or transabdominal ultrasound. LS Means based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World), and Baseline values as covariate.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Uterine Fibroid Volume with Relugolix plus E2/NETA | ||||||||||||
Comparison groups |
Relugolix plus E2/NETA (Group A) v Placebo (Group C)
|
||||||||||||
Number of subjects included in analysis |
193
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [22] | ||||||||||||
P-value |
= 0.2153 [23] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
-10
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-25.8 | ||||||||||||
upper limit |
5.8 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
8.03
|
||||||||||||
Notes [22] - Based on analysis of covariance model with treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, ≥ 225 mL), geographic region (North America, Rest of World), and Baseline values as covariate. [23] - Assessed at a two-sided α = 0.05 significance level. |
|
|||||||||||||
End point title |
Percent Change From Baseline At Week 24 In Uterine Volume [24] | ||||||||||||
End point description |
The volume of the uterus was measured by transvaginal or transabdominal ultrasound. LS means for test of difference is Relugolix plus E2/NETA minus Placebo at Week 24 is based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World), and Baseline values as covariate.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Uterine Volume with Relugolix plus E2/NETA | ||||||||||||
Comparison groups |
Relugolix plus E2/NETA (Group A) v Placebo (Group C)
|
||||||||||||
Number of subjects included in analysis |
195
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [25] | ||||||||||||
P-value |
= 0.0078 [26] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
-12.2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-21.3 | ||||||||||||
upper limit |
-3.2 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
4.57
|
||||||||||||
Notes [25] - Based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, ≥ 225 mL), geographic region (North America, Rest of World), and Baseline values as covariate. [26] - Assessed at a two- sided α = 0.05 significance level. |
|
|||||||||||||
End point title |
Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5) [27] | ||||||||||||
End point description |
The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) Bleeding and Pelvic Discomfort (BPD) Scale has been derived from the UFS-QoL Symptoms Scale. The scale consists of the following 3 symptoms proximal to uterine fibroids: Heavy bleeding during your menstrual period (Question [Q] 1), passing blood clots during your menstrual period (Q2), and feeling tightness or pressure in your pelvic area (Q5). The lowest possible raw score is 3 and the highest possible raw score is 15. The possible raw score range is 12. The following formula was used to transform the raw score to a normalized score:
Transformed Score = [(Actual raw score – lowest possible raw score)/(Possible raw score range)] * 100
Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
Notes [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary efficacy analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
UFS-QoL BPD Score with Relugolix plus E2/NETA | ||||||||||||
Comparison groups |
Placebo (Group C) v Relugolix plus E2/NETA (Group A)
|
||||||||||||
Number of subjects included in analysis |
191
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [28] | ||||||||||||
P-value |
< 0.0001 [29] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
-33.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-41.2 | ||||||||||||
upper limit |
-25.5 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
3.98
|
||||||||||||
Notes [28] - Treatment difference is Relugolix plus E2/NETA minus Placebo based on mixed-effect model with treatment, visit, region, Baseline MBL, and treatment by visit interaction included as fixed effects. The multiple visits for each participant were the repeated measures as random effect within each participant and an unstructured covariance. [29] - Assessed at a two-sided α = 0.05 significance level. |
|
|||||||||||||
End point title |
Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1-L4) As Assessed By DXA [30] | ||||||||||||
End point description |
Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at the lumbar spine (L1, L2, L3, and L4) at Baseline and at Week 12. The scans were read by the central radiology laboratory in accordance with the imaging charter. The same DXA machine was used at the local imaging center at each site and operated in the same scan mode for all images procured for an individual participant. All images were submitted for central reading. The central radiology laboratory collected and evaluated all DXA scans for acceptability and measured BMD. The LS means were based on a mixed-effect model with visit, region, Baseline menstrual blood loss volume, age at Baseline, body mass index at Baseline, bone mineral density at Baseline, race, and treatment by visit interaction included as fixed effects.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline, Week 12
|
||||||||||||
Notes [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary analyses compared Relugolix plus E2/NETA with Relugolix plus Delayed E2/NETA at Week 12. Therefore, only the Relugolix plus E2/NETA and Relugolix plus Delayed E2/NETA arms are presented. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1-L4), Total Hip, And Femoral Neck As Assessed By DXA [31] | |||||||||||||||||||||
End point description |
BMD was assessed by DXA at the lumbar spine (L1, L2, L3, and L4), total hip, and femoral neck (same leg across participants) at Baseline and at Week 24. The scans were read by the central radiology laboratory in accordance with the imaging charter. The same DXA machine was used at the local imaging center at each site and operated in the same scan mode for all images procured for an individual participant. All images were submitted for central reading. The central radiology laboratory collected and evaluated all DXA scans for acceptability and measured BMD. The LS means were based on a mixed-effect model with visit, region, Baseline menstrual blood loss volume, age at Baseline, body mass index at Baseline, bone mineral density at Baseline, race, and treatment by visit interaction included as fixed effects. For Relugolix plus E2/NETA Lumbar Spine (L1-L4), n=95.
|
|||||||||||||||||||||
End point type |
Other pre-specified
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
Notes [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary analyses compared Relugolix plus E2/NETA with Placebo at Week 24. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
||||||||||||||||||||||
|
||||||||||||||||||||||
Notes [32] - For Lumbar Spine (L1-L4), N=95 |
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12 [33] | ||||||||||||
End point description |
An adverse event was defined as an unfavourable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing were combined to describe vasomotor symptoms. Participants with multiple events for a given preferred term were counted only once for each preferred term. Reported CI based on exact binomial 95% CI (Clopper-Pearson).
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline through Week 12
|
||||||||||||
Notes [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the secondary analysis compared Relugolix plus E2/NETA with Relugolix plus Delayed E2/NETA at Week 12. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Vasomotor Symptoms Through Week 12 | ||||||||||||
Comparison groups |
Relugolix plus E2/NETA (Group A) v Relugolix plus Delayed E2/NETA (Group B)
|
||||||||||||
Number of subjects included in analysis |
252
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [34] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Risk ratio (RR) | ||||||||||||
Point estimate |
0.16
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.07 | ||||||||||||
upper limit |
0.33 | ||||||||||||
Notes [34] - Relative risk ratio is Relugolix plus E2/NETA over Relugolix plus Delayed E2/NETA. |
|
|||||||||||||
End point title |
Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24 [35] | ||||||||||||
End point description |
An adverse event was defined as an unfavourable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing were combined to describe vasomotor symptoms. Participants with multiple events for a given preferred term were counted only once for each preferred term. Reported percentages based on the total number of participants in each treatment group.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Baseline through Week 24
|
||||||||||||
Notes [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, the pre-specified secondary analyses compared Relugolix plus E2/NETA with Placebo. Therefore, only the Relugolix plus E2/NETA and Placebo arms are presented. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Predose Trough Concentrations Of Relugolix And Norethindrone (NET) In The Relugolix Plus E2/NETA Group At Week 24 [36] | ||||||||||||
End point description |
Blood samples for determination of relugolix and NET plasma concentrations were collected predose at Week 24. On clinic visit days, participants were instructed to hold their dose of study drug until blood samples for determination of plasma drug concentrations were collected at the clinic and to record the time of their previous dose (that is, the time they took their dose on the day before the clinic visit). Relugolix and NET plasma concentrations were determined using validated bioanalytical methodology. The lower limit of quantification for relugolix and NET plasma concentrations were both 0.05 nanograms (ng)/mL. Concentrations below the quantification limit (BQL) were set to 0 for analysis of summary statistics.
|
||||||||||||
End point type |
Other pre-specified
|
||||||||||||
End point timeframe |
Week 24
|
||||||||||||
Notes [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, only Relugolix plus E2/NETA concentrations are presented. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Predose Trough Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group At Week 24 [37] | ||||||||
End point description |
Blood samples for determination of estradiol serum concentrations were collected predose at Baseline and Week 24. On clinic visit days, participants were instructed to hold their dose of study drug until blood samples for determination of serum concentrations were collected at the clinic and to record the time of their previous dose (that is, the time they took their dose on the day before the clinic visit). Summary data for estradiol trough serum concentrations are descriptive only and values were not baseline-adjusted, which is an approach that has been employed for assessment of endogenously- produced substances upon exogenous administration. Estradiol serum concentrations were determined using validated bioanalytical methodology. The lower limit of quantification for estradiol serum concentration was 2.5 picograms (pg)/mL. Concentrations BQL were set to 0 for analysis of summary statistics.
|
||||||||
End point type |
Other pre-specified
|
||||||||
End point timeframe |
Week 24
|
||||||||
Notes [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, only Relugolix plus E2/NETA concentrations are presented. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group [38] | ||||||||
End point description |
Blood samples for determination of estradiol concentrations were collected predose at Baseline and at Weeks 4, 12, and 24 and were analyzed at a central laboratory using a standard, validated clinical methodology. For pharmacokinetic analysis of estradiol, a separate pharmacokinetic sample was obtained to be analyzed at the bioanalytical laboratory. The lower limit of quantification for estradiol was 19 pg/mL. Concentrations BQL were set to 0 for analysis of summary statistics. Data reported as pg/mL.
|
||||||||
End point type |
Other pre-specified
|
||||||||
End point timeframe |
Baseline, Week 24
|
||||||||
Notes [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: As per the objective of the study, only Relugolix plus E2/NETA concentrations are presented. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From Day 1 to End of Study (24 Weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
One participant was randomized to Group A, but was dispensed and received Group B therapy. Per the statistical analysis plan, data from this participant was included in Group A for efficacy analyses and in Group B for safety analyses.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Relugolix plus E2/NETA (Group A)
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Reporting group description |
Relugolix co-administered with E2/NETA for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Relugolix plus Delayed E2/NETA (Group B)
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Reporting group description |
Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo (Group C)
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Reporting group description |
Relugolix placebo co-administered with E2/NETA placebo for 24 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |